Viral infection and spread are inhibited by the polyubiquitination and downregulation of TRPV2 channel by the interferon-stimulated gene TRIM21.

Interferon (IFN) contributes to the host's antiviral response by inducing IFN-stimulated genes (ISGs). However, their functional targets and the mechanism of action remain elusive. Here, we report that one such ISG, TRIM21, interacts with and degrades the TRPV2 channel in myeloid cells, reducing its expression and providing host protection against viral infections. Moreover, viral infection upregulates TRIM21 in paracrine and autocrine manners, downregulating TRPV2 in neighboring cells to prevent viral spread to uninfected cells. Consistently, the Trim21-/- mice are more susceptible to HSV-1 and VSV infection than the Trim21+/+ littermates, in which viral susceptibility is rescued by inhibition or deletion of TRPV2. Mechanistically, TRIM21 catalyzes the K48-linked ubiquitination of TRPV2 at Lys295. TRPV2K295R is resistant to viral-infection-induced TRIM21-dependent ubiquitination and degradation, promoting viral infection more profoundly than wild-type TRPV2 when reconstituted into Lyz2-Cre;Trpv2fl/fl myeloid cells. These findings characterize targeting the TRIM21-TRPV2 axis as a conducive strategy to control viral spread to bystander cells.

Disulfiram ameliorates STING/MITA-dependent inflammation and autoimmunity by targeting RNF115.

STING (also known as MITA) is an adaptor protein that mediates cytoplasmic DNA-triggered signaling, and aberrant activation of STING/MITA by cytosolic self-DNA or gain-of-function mutations causes severe inflammation. Here, we show that STING-mediated inflammation and autoimmunity are promoted by RNF115 and alleviated by the RNF115 inhibitor disulfiram (DSF). Knockout of RNF115 or treatment with DSF significantly inhibit systemic inflammation and autoimmune lethality and restore immune cell development in Trex1-/- mice and STINGN153S/WT bone marrow chimeric mice. In addition, knockdown or pharmacological inhibition of RNF115 substantially downregulate the expression of IFN-α, IFN-γ and proinflammatory cytokines in PBMCs from patients with systemic lupus erythematosus (SLE) who exhibit high concentrations of dsDNA in peripheral blood. Mechanistically, knockout or inhibition of RNF115 impair the oligomerization and Golgi localization of STING in various types of cells transfected with cGAMP and in organs and cells from Trex1-/- mice. Interestingly, knockout of RNF115 inhibits the activation and Golgi localization of STINGN153S as well as the expression of proinflammatory cytokines in myeloid cells but not in endothelial cells or fibroblasts. Taken together, these findings highlight the RNF115-mediated cell type-specific regulation of STING and STINGN153S and provide potential targeted intervention strategies for STING-related autoimmune diseases.

A case report of Williams syndrome with main clinical manifestation of hypercalcemia and gastrointestinal bleeding as the main clinical manifestations, and with an accompanying literature review.

BACKGROUND: Williams syndrome is an autosomal dominant multisystem disorder caused by a 1.5-1.8 Mb deletion on chromosome 7q11.23. It is characterized by facial deformations, cardiovascular abnormalities, developmental delays, gastrointestinal manifestations, and endocrine disorders. CASE DESCRIPTION: A 1-year-old child presenting with developmental delays, special facial features, gastrointestinal bleeding, renal calcium deposition, and hypotonia was admitted to the hospital for "hypercalcemia and gastrointestinal bleeding." Genetic testing showed a deletion mutation in the 7q11.23 region. Currently, the child receiving treatment to promote calcium excretion and rehabilitation training, but hypercalcemia has recurred. CONCLUSION: The clinical phenotype of Williams syndrome is complex, and different severities, characterized by developmental delays, facial deformities, cardiovascular abnormalities, gastrointestinal symptoms and endocrine disorders, should be considered in children. The syndrome may require thorough genetic testing for diagnosis and early intervention treatment to improve patient quality of life.

The E3 ubiquitin ligase ARIH1 promotes antiviral immunity and autoimmunity by inducing mono-ISGylation and oligomerization of cGAS.

The cytosolic DNA sensor cyclic GMP-AMP synthase (cGAS) plays a critical role in antiviral immunity and autoimmunity. The activity and stability of cGAS are fine-tuned by post-translational modifications. Here, we show that ariadne RBR E3 ubiquitin protein ligase 1 (ARIH1) catalyzes the mono-ISGylation and induces the oligomerization of cGAS, thereby promoting antiviral immunity and autoimmunity. Knockdown or knockout of ARIH1 significantly inhibits herpes simplex virus 1 (HSV-1)- or cytoplasmic DNA-induced expression of type I interferons (IFNs) and proinflammatory cytokines. Consistently, tamoxifen-treated ER-Cre;Arih1fl/fl mice and Lyz2-Cre; Arih1fl/fl mice are hypersensitive to HSV-1 infection compared with the controls. In addition, deletion of ARIH1 in myeloid cells alleviates the autoimmune phenotypes and completely rescues the autoimmune lethality caused by TREX1 deficiency. Mechanistically, HSV-1- or cytosolic DNA-induced oligomerization and activation of cGAS are potentiated by ISGylation at its K187 residue, which is catalyzed by ARIH1. Our findings thus reveal an important role of ARIH1 in innate antiviral and autoimmune responses and provide insight into the post-translational regulation of cGAS.

The Transient Receptor Potential Vanilloid 2 (TRPV2) Channel Facilitates Virus Infection Through the Ca2+ -LRMDA Axis in Myeloid Cells.

The transient receptor potential vanilloid 2 (TRPV2) channel is a nonselective cation channel that has been implicated in multiple sensory processes in the nervous system. Here, it is shown that TRPV2 in myeloid cells facilitates virus penetration by promoting the tension and mobility of cell membrane through the Ca2+ -LRMDA axis. Knockout of TRPV2 in myeloid cells or inhibition of TRPV2 channel activity suppresses viral infection and protects mice from herpes simplex virus 1 (HSV-1) and vesicular stomatitis virus (VSV) infection. Reconstitution of TRPV2 but not the Ca2+ -impermeable mutant TRPV2E572Q into LyZ2-Cre;Trpv2fl/fl bone marrow-derived dendritic cells (BMDCs) restores viral infection. Mechanistically, knockout of TRPV2 in myeloid cells inhibits the tension and mobility of cell membrane and the penetration of viruses, which is restored by reconstitution of TRPV2 but not TRPV2E572Q . In addition, knockout of TRPV2 leads to downregulation of Lrmda in BMDCs and BMDMs, and knockdown of Lrmda significantly downregulates the mobility and tension of cell membrane and inhibits viral infections in Trpv2fl/fl but not LyZ2-Cre;Trpv2fl/fl BMDCs. Consistently, complement of LRMDA into LyZ2-Cre;Trpv2fl/fl BMDCs partially restores the tension and mobility of cell membrane and promotes viral penetration and infection. These findings characterize a previously unknown function of myeloid TRPV2 in facilitating viral infection though the Ca2+ -LRMDA axis.

RNF115 Inhibits the Post-ER Trafficking of TLRs and TLRs-Mediated Immune Responses by Catalyzing K11-Linked Ubiquitination of RAB1A and RAB13.

The subcellular localization and intracellular trafficking of Toll-like receptors (TLRs) critically regulate TLRs-mediated antimicrobial immunity and autoimmunity. Here, it is demonstrated that the E3 ubiquitin ligase RNF115 inhibits the post-endoplasmic reticulum (ER) trafficking of TLRs and TLRs-mediated immune responses by catalyzing ubiquitination of the small GTPases RAB1A and RAB13. It is shown that the 14-3-3 chaperones bind to AKT1-phosphorylated RNF115 and facilitate RNF115 localizing on the ER and the Golgi apparatus. RNF115 interacts with RAB1A and RAB13 and catalyzes K11-linked ubiquitination on the Lys49 and Lys61 residues of RAB1A and on the Lys46 and Lys58 residues of RAB13, respectively. Such a modification impairs the recruitment of guanosine diphosphate (GDP) dissociation inhibitor 1 (GDI1) to RAB1A and RAB13, a prerequisite for the reactivation of RAB proteins. Consistently, knockdown of RAB1A and RAB13 in Rnf115+/+ and Rnf115-/- cells markedly inhibits the post-ER and the post-Golgi trafficking of TLRs, respectively. In addition, reconstitution of RAB1AK49/61R or RAB13K46/58R into Rnf115+/+ cells but not Rnf115-/- cells promotes the trafficking of TLRs from the ER to the Golgi apparatus and from the Golgi apparatus to the cell surface, respectively. These findings uncover a common and step-wise regulatory mechanism for the post-ER trafficking of TLRs.

IL-36γ and IL-36Ra Reciprocally Regulate NSCLC Progression by Modulating GSH Homeostasis and Oxidative Stress-Induced Cell Death.

The balance between antioxidants and reactive oxygen species (ROS) critically regulates tumor initiation and progression. However, whether and how the tumor-favoring redox status is controlled by cytokine networks remain poorly defined. Here, it is shown that IL-36γ and IL-36Ra reciprocally regulate the progression of non-small cell lung cancer (NSCLC) by modulating glutathione metabolism and ROS resolution. Knockout, inhibition, or neutralization of IL-36γ significantly inhibits NSCLC progression and prolongs survival of the KrasLSL-G12D/+ Tp53fl/fl and KrasLSL-G12D/+ Lkb1fl/fl mice after tumor induction, whereas knockout of IL-36Ra exacerbates tumorigenesis in these NSCLC mouse models and accelerates death of mice. Mechanistically, IL-36γ directly upregulates an array of genes involved in glutathione homeostasis to reduce ROS and prevent oxidative stress-induced cell death, which is mitigated by IL-36Ra or IL-36γ neutralizing antibody. Consistently, IL-36γ staining is positively and negatively correlated with glutathione biosynthesis and ROS in human NSCLC tumor biopsies, respectively. These findings highlight essential roles of cytokine networks in redox for tumorigenesis and provide potential therapeutic strategy for NSCLC.

Effects of simvastatin on aortic vascular endothelial cell apoptosis and Bcl-2 protein expression in a rat model of atherosclerosis / 南方医科大学学报

<p><b>OBJECTIVE</b>To explore the effects of simvastatin on vascular endothelial cell apoptosis and Bcl-2 protein expression in the aorta in a rat model of atherosclerosis.</p><p><b>METHODS</b>Thirty-six rats were randomized into control group (n=10), atherosclerosis model group (n=13) and simvastatin intervention group (n=13). In the latter two groups, rat models of atherosclerosis were established by intraperitoneal injection of vitamin D3 combined with high-fat feeding for 6 weeks, and the control rats were fed with regular diet. In the intervention group, the rats were further fed with high-fat diet with daily simvastatin treatment for 4 weeks. After the treatments, the pathological changes and plaque in the thoracic aorta were observed, and the expression of Bcl-2 protein was detected with immunohistochemistry. TUNEL assay was used to determine the apoptosis index (AI) of the vascular endothelial cells.</p><p><b>RESULTS</b>Compared with that in the control group, Bcl-2 protein expression in the aorta of atherosclerotic rats was significantly decreased (P<0.05); simvastatin treatment obviously increased the expression of Bcl-2 protein in atherosclerotic rats (P<0.05) to a level similar to that in the control group. The AI was the highest in the model group (P<0.05) and comparable between the control and simvastatin treatment group.</p><p><b>CONCLUSION</b>The therapeutic effect of simvastatin against atherosclerosis is probably mediated by up-regulation of Bcl-2 protein, which inhibits vascular endothelial cell apoptosis in rats with aortic atherosclerosis.</p>

Variations in the extensor grooves on the radial styloid process in Chinese population.

PURPOSE: The aim was to provide anatomical data for local blocking treatment of de Quervain's disease through investigating features and classification of the first extensor groove on the radial styloid process. METHODS: Two hundred and eighty-four specimens of the intact distal extremity of dry radii from Chinese corpses were investigated and measured systematically in this study. Morphological features of the extensor grooves on the radial styloid process were observed by visual inspection. Correlation parameters of variability were measured with a vernier caliper. RESULTS: The study showed that the most prevalent group was Type I (the extensor groove that was deep and divided into two sub-grooves by a tiny bony ridge) accounting for 63.73 % (181 specimens). Seventy-nine specimens belonged to Type II (the extensor groove without the tiny bony ridge) accounting for 27.82 % and 24 specimens belonged to Type III (almost without any extensor groove on the radius) accounting for 8.45 %. The distance between the processus of the palmar bony ridge and the processus of the dorsal bony ridge (defined as AC) was 11.55 ± 1.32 mm. The distance between the processus of the palmar bony ridge and the sharp point of the styloid process of the radius (defined as AB) was 17.09 ± 1.99 mm. CONCLUSIONS: The extensor groove could provide a subjective safe operation range for the steroid injections, which could be defined depending on the bony landmarks, which are easy to identify in the body surface. This anatomical variation is important in the management of de Quervain's disease.

A modified sagittal spine postural classification and its relationship to deformities and spinal mobility in a chinese osteoporotic population.

BACKGROUND: Abnormal posture and spinal mobility have been demonstrated to cause functional impairment in the quality of life, especially in the postmenopausal osteoporotic population. Most of the literature studies focus on either thoracic kyphosis or lumbar lordosis, but not on the change of the entire spinal alignment. Very few articles reported the spinal alignment of Chinese people. The purpose of this study was threefold: to classify the spinal curvature based on the classification system defined by Satoh consisting of the entire spine alignment; to identify the change of trunk mobility; and to relate spinal curvature to balance disorder in a Chinese population. METHODOLOGY/PRINCIPAL FINDINGS: 450 osteoporotic volunteers were recruited for this study. Spinal range of motion and global curvature were evaluated noninvasively using the Spinal-Mouse® system and sagittal postural deformities were characterized. RESULTS: We found a new spine postural alignment consisting of an increased thoracic kyphosis and decreased lumbar lordosis which we classified as our modified round back. We did not find any of Satoh's type 5 classification in our population. Type 2 sagittal alignment was the most common spinal deformity (38.44%). In standing, thoracic kyphosis angles in types 2 (58.34°) and 3 (58.03°) were the largest and lumbar lordosis angles in types 4 (13.95°) and 5 (-8.61°) were the smallest. The range of flexion (ROF) and range of flexion-extension (ROFE) of types 2 and 3 were usually greater than types 4 and 5, with type 1 being the largest. CONCLUSIONS/SIGNIFICANCE: The present study classified and compared for the first time the mobility, curvature and balance in a Chinese population based on the entire spine alignment and found types 4 and 5 to present the worst balance and mobility. This study included a new spine postural alignment classification that should be considered in future population studies.

[Treatment of displaced humeral supracondylar fractures in children with external fixation using plaster or splint].

OBJECTIVE: To investigate the therapeutic effects of closed reduction and external fixation (plaster or splint) for the treatment of displaced humeral supracondylar fractures in children. METHODS: From March 2007 to September 2009,33 children (15 female and 18 male) with humeral supracondylar fractures treated in our hospital, ranging from 3 to 12 years old with an average of 6.4 years old. All the fractures were extension-type injuries, the flexion injures were excluded in our study. The humeral supracondylar fractures were classified according to Gartland classification. There were 21 Type H and 12 type III. In the initial treatment, all the patients were treated with closed reduction and external immobilization. The blood supply of the damaged upper extremity was evaluated before and after treatment. Clinical assessment was obtained at final follow-up using Flynn criteria, and radiologic assessment was obtained using Baumann and lateral humerocapitellar angles. RESULTS: All the children were treated successfully with closed reduction in the initial time; 24 children maintained limb alignment by external immobilization. Nine patients lost position due to the swelling around the elbow which affected unstable external fixation during the follow-up, 5 of which were treated with a repeated closed reduction and internal fixation with Kirschner wires, 4 of which were treated with traction. Thirty-one patients had a satisfactory outcome and 2 patients had an unsatisfactory outcome according to the Flynn criteria at the latest follows-up. CONCLUSION: Closed reduction and external stabilization is an important method for the treatment of displaced humeral supracondylar fractures in children. Making regular follow-up visits after closed reduction and casting is important for patients to maintain acceptable alignment, avoid complications and diagnose any loss of reduction.

Treatment of displaced humeral supracondylar fractures in children with external fixation using plaster or splint / 中国骨伤

<p><b>OBJECTIVE</b>To investigate the therapeutic effects of closed reduction and external fixation (plaster or splint) for the treatment of displaced humeral supracondylar fractures in children.</p><p><b>METHODS</b>From March 2007 to September 2009,33 children (15 female and 18 male) with humeral supracondylar fractures treated in our hospital, ranging from 3 to 12 years old with an average of 6.4 years old. All the fractures were extension-type injuries, the flexion injures were excluded in our study. The humeral supracondylar fractures were classified according to Gartland classification. There were 21 Type H and 12 type III. In the initial treatment, all the patients were treated with closed reduction and external immobilization. The blood supply of the damaged upper extremity was evaluated before and after treatment. Clinical assessment was obtained at final follow-up using Flynn criteria, and radiologic assessment was obtained using Baumann and lateral humerocapitellar angles.</p><p><b>RESULTS</b>All the children were treated successfully with closed reduction in the initial time; 24 children maintained limb alignment by external immobilization. Nine patients lost position due to the swelling around the elbow which affected unstable external fixation during the follow-up, 5 of which were treated with a repeated closed reduction and internal fixation with Kirschner wires, 4 of which were treated with traction. Thirty-one patients had a satisfactory outcome and 2 patients had an unsatisfactory outcome according to the Flynn criteria at the latest follows-up.</p><p><b>CONCLUSION</b>Closed reduction and external stabilization is an important method for the treatment of displaced humeral supracondylar fractures in children. Making regular follow-up visits after closed reduction and casting is important for patients to maintain acceptable alignment, avoid complications and diagnose any loss of reduction.</p>

[Retrospective analysis of 75 cases of flap transplantations in children].

OBJECTIVE: To investigate the therapeutic effect of flap transplantation in repairing soft tissue defects of children. METHODS: From January 1997 to May 2002, 75 cases of different soft tissue defects (52 males and 23 females, with the age of 3-14 years) were repaired by axial and non-axial flaps transfer, and axial flaps transplantation by microvascular anastomosis. The flaps area ranged from 3 cm x 5 cm to 15 cm x 42 cm. Emergency operation was performed in 26 cases and secondary operation in 49 cases (infective wound such as osteomyelitis and plate extra-exposed of fracture). The defect regions included the forearm, back of the hand, thumb, index finger, leg and foot. The types of flap graft and application range included 39 cases of axial flaps transfer or transplantation (27 cases of along- or contra-transfer of transplantation and 12 cases of microvascular anastomosis). The non-axial flaps transfer were designed along- or contra-transfer near the wound area in 36 cases. The ratio of length to width was 2.5:1-3.5:1 in 27 cases, and larger than 3.5:1 in 9 cases. Adequate anesthesia method should be chosen according to the characteristics of children, non-traumatic operating during surgery and postoperative supervision and nursing of flaps should also be paid enough attention. RESULTS: After operation, blood circulation crisis occurred in 2 cases (1 case of artery failure and 1 case of vein failure). The flaps survived in 37 cases and partially survived in 1 case and necrosed in 1 case. The survival rate was 96.2%. The postoperative follow-up period was 3 to 60 months, the blood supply, elasticity and texture of flaps were good. The effect of repair was satisfactory. CONCLUSION: Different types of transplantation of blood-supply of flaps may repair the different types of soft tissue defects in children. Free flap transplantation is safe and beneficial in children, different defects of soft tissue were repaired by axial and non-axial flaps transfer, axial flaps transplantation by microvascular anastomosis. Non-traumatic operating and postoperative supervision and nursing of flaps should also be paid enough attention.

[Surgical repair of major vascular injuries in the extremities complicated by other injuries: retrospective analysis of 67 cases].

OBJECTIVE: To retrospectively analyze the surgical repair of injured major vessels in the extremities complicated by multiple other injuries. METHODS: According to different time lengths of sustaining ischemia, sites of the major vascular injuries and conditions of other injuries, 91 operations for end-to-end anastomosis, vessel grafting and repair, ligation and shunting respectively were performed on the 67 patients. RESULTS: Except for 2 fatal cases (one due to preoperative brain hernia and hemorrhagic shock, the other to thyroid crisis during operation), all other cases survived the operations. Vascular crisis occurred in 3 cases (2 arterial spasm and 1 venous crisis) 6, 7 and 12 h respectively after the operations, which were relieved by appropriate treatments and surgical explorations. One patient developed pneumonia and acute renal failure with polyuria at postoperative days 7 and 4 respectively, but full recovery was achieved. CONCLUSIONS: For patients with major vascular injuries in the extremity complicated by multiple other injuries, timely revascularization of the extremities should be performed during or immediately after emergency operations of the vital organs. Particular attention should be given to the diagnosis and repair of closed major vascular injuries in such patients, who need to be monitored for blood coagulation during operation and should receive due post-operative anti-coagulation treatment.